Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 Oct 2024
23 Oct 2024
Historique:
received:
05
05
2023
accepted:
10
10
2024
medline:
23
10
2024
pubmed:
23
10
2024
entrez:
22
10
2024
Statut:
epublish
Résumé
Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyze the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We find that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyzes of public data from several multi-children families and from 1934 familial quads confirm this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in mutation transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyzes of all the data consistently suggest that the germline has a balanced 50:50 lineage allocation from the first two blastomeres.
Identifiants
pubmed: 39438473
doi: 10.1038/s41467-024-53485-x
pii: 10.1038/s41467-024-53485-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9117Subventions
Organisme : NINDS NIH HHS
ID : UG3 NS132128
Pays : United States
Organisme : NINDS NIH HHS
ID : UG3 NS132146
Pays : United States
Organisme : Simons Foundation
ID : 399558
Organisme : Simons Foundation
ID : 399558
Organisme : National Research Foundation of Korea (NRF)
ID : 2022R1A6A3A03055692
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : NS132128
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : NS132146
Informations de copyright
© 2024. The Author(s).
Références
Wen, L. & Tang, F. Human germline cell development: from the perspective of single-cell sequencing. Mol. Cell 76, 320–328 (2019).
doi: 10.1016/j.molcel.2019.08.025
pubmed: 31563431
Samuels, M. E. & Friedman, J. M. Genetic mosaics and the germ line lineage. Genes (Basel) 6, 216–237 (2015).
doi: 10.3390/genes6020216
pubmed: 25898403
Zheng, C. J., Luebeck, E. G., Byers, B. & Moolgavkar, S. H. On the number of founding germ cells in humans. Theor. Biol. Med Model 2, 32 (2005).
doi: 10.1186/1742-4682-2-32
pubmed: 16120211
pmcid: 1215522
Rahbari, R. et al. Timing, rates and spectra of human germline mutation. Nat. Genet 48, 126–133 (2016).
doi: 10.1038/ng.3469
pubmed: 26656846
Fasching, L. et al. Early developmental asymmetries in cell lineage trees in living individuals. Science 371, 1245–1248 (2021).
doi: 10.1126/science.abe0981
pubmed: 33737484
pmcid: 8324008
Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018).
doi: 10.1126/science.aan8690
pubmed: 29217587
Coorens, T. H. H. et al. Extensive phylogenies of human development inferred from somatic mutations. Nature 597, 387–392 (2021).
doi: 10.1038/s41586-021-03790-y
pubmed: 34433963
Park, S. et al. Clonal dynamics in early human embryogenesis inferred from somatic mutation. Nature 597, 393–397 (2021).
doi: 10.1038/s41586-021-03786-8
pubmed: 34433967
Spencer Chapman, M. et al. Lineage tracing of human development through somatic mutations. Nature 595, 85–90 (2021).
doi: 10.1038/s41586-021-03548-6
pubmed: 33981037
Jonsson, H. et al. Multiple transmissions of de novo mutations in families. Nat. Genet 50, 1674–1680 (2018).
doi: 10.1038/s41588-018-0259-9
pubmed: 30397338
Sasani, T. A. et al. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. Elife 8, e46922 (2019).
doi: 10.7554/eLife.46922
pubmed: 31549960
pmcid: 6759356
Acuna-Hidalgo, R. et al. Post-zygotic point mutations are an underrecognized source of De Novo genomic variation. Am. J. Hum. Genet 97, 67–74 (2015).
doi: 10.1016/j.ajhg.2015.05.008
pubmed: 26054435
pmcid: 4571017
Campbell, I. M. et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet 95, 173–182 (2014).
doi: 10.1016/j.ajhg.2014.07.003
pubmed: 25087610
pmcid: 4129404
Kaplanis, J. et al. Genetic and chemotherapeutic influences on germline hypermutation. Nature 605, 503–508 (2022).
doi: 10.1038/s41586-022-04712-2
pubmed: 35545669
pmcid: 9117138
Jonsson, H. et al. Parental influence on human germline de novo mutations in 1548 trios from Iceland. Nature 549, 519–522 (2017).
doi: 10.1038/nature24018
pubmed: 28959963
An, J. Y. et al. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362, eaat6576 (2018).
doi: 10.1126/science.aat6576
pubmed: 30545852
pmcid: 6432922
Junyent, S. et al. The first two blastomeres contribute unequally to the human embryo. Cell 187, 2838–2854.e17 (2024).
doi: 10.1016/j.cell.2024.04.029
pubmed: 38744282
Chen, D. et al. Human primordial germ cells are specified from lineage-primed progenitors. Cell Rep. 29, 4568–4582.e4565 (2019).
doi: 10.1016/j.celrep.2019.11.083
pubmed: 31875561
pmcid: 6939677
Kobayashi, T. & Surani, M. A. On the origin of the human germline. Development 145, dev150433 (2018).
doi: 10.1242/dev.150433
pubmed: 30037844
Saitou, M. & Hayashi, K. Mammalian in vitro gametogenesis. Science 374, eaaz6830 (2021).
doi: 10.1126/science.aaz6830
pubmed: 34591639
De Felici, M. in Oogenesis (eds G. Coticchio, D. F. Albertini, & L. De Santis) 19-37 (Springer London, 2013).
Sarangi, V. et al. All2: a tool for selecting mosaic mutations from comprehensive multi-cell comparisons. PLoS Comput Biol. 18, e1009487 (2022).
doi: 10.1371/journal.pcbi.1009487
pubmed: 35442945
pmcid: 9060341
McKenna, A. et al. The Genome analysis toolkit: a mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res 20, 1297–1303 (2010).
doi: 10.1101/gr.107524.110
pubmed: 20644199
pmcid: 2928508
Kim, S. et al. Strelka2: fast and accurate calling of germline and somatic variants. Nat. Methods 15, 591–594 (2018).
doi: 10.1038/s41592-018-0051-x
pubmed: 30013048
Dou, Y. et al. Accurate detection of mosaic variants in sequencing data without matched controls. Nat. Biotechnol. 38, 314–319 (2020).
doi: 10.1038/s41587-019-0368-8
pubmed: 31907404
pmcid: 7065972